There is strong evidence that a combination of inherited genotypes and hormone exposures influenced breast cancer risk. Furthermore, inherited genotypes involved in the metabolism of steroid hormones may also modify a woman's risk of developing breast cancer. Knowledge about interactions of these factors in breast cancer etiology may improve the ability to identify women at increased breast cancer risk. This knowledge may in turn be used to target women for breast cancer prevention or treatment strategies. We propose a population-based case-control study that will directly address the complex, multi-factorial etiology of breast cancer that involves the interaction of genotypes and hormonal risk factors. These hormonal factors include endogenous exposures measured by parity-related events, and exogenous exposures to compounds such as estrogen replacement therapy (ERT). This study will address a number of specific hypothesis. First, we will evaluate whether candidate susceptibility genotypes are associated with breast cancer in a case-control analysis. The genes of primary interest will be CYP1A1, CYP3A4, and glutathione-S-transferase mu and theta genes, which are involved in the metabolism of steroid hormones. Second, we will evaluate whether genotypes and other reproductive risk factors interact in breast cancer etiology, and whether knowledge of genotypes will improve our understanding of breast cancer etiology once hormonal risk factors (e.g., reproductive history or ERT) are known. Third, we will evaluate whether the genetic and hormonal etiology of breast cancer differs by race. In order to address these hypotheses, we will undertake a study in the Greater Delaware Valley using an existing network of hospitals to identify a population-based sample of cases and random digit dialed controls. The sample will consist of 1200 White and 1200 Black subjects. Risk-factor information will be obtained from a telephone interview, a biosample containing DNA will be collected using a non-invasive cheek swab method. and pathology information will be collected using standardized medical record abstraction. Analyses will be undertaken to evaluate the roll of candidate genotypes and hormonal risk factors in breast cancer etiology by race. These analyses will allow us to examine genotype by hormonal interactions in breast cancer etiology.